1. Translocator protein-mediated fast-onset antidepressant-like and memory-enhancing effects in chronically stressed mice.
- Author
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Shang, Chao, Yao, Ru-Meng, Guo, Ying, Ding, Zhen-Chun, Sun, Li-Jun, Ran, Yu-Hua, Xue, Rui, Wang, Huai-Shan, Zhang, Jian-Min, Zhang, You-Zhi, Zhang, Li-Ming, and Li, Yun-Feng
- Subjects
TRANSLOCATOR proteins ,MTOR protein ,PYRAMIDAL neurons ,MICE ,PREFRONTAL cortex ,COGNITIVE testing ,DENDRITIC spines ,STEROID metabolism ,MEMORY ,ANTIDEPRESSANTS ,FRONTAL lobe ,ANIMAL behavior ,RESEARCH ,NEURONS ,ADRENOCORTICAL hormones ,ANIMAL experimentation ,CHRONIC diseases ,PURINES ,RESEARCH methodology ,CELL receptors ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,PSYCHOLOGICAL stress ,TRANQUILIZING drugs ,PHARMACODYNAMICS ,PSYCHOLOGICAL factors ,CELL physiology - Abstract
Background: Fast-acting and cognitive-enhancing antidepressants are desperately needed. Activation of translocator protein (18 kDa, TSPO) is a novel strategy for developing potential antidepressants, but there are no data available on the onset time of TSPO ligands. This study aimed to investigate the fast-onset antidepressant actions of AC-5216, a selective TSPO ligand, in TSPO knock-out (KO) mice.Methods: TSPO wild-type (WT) and KO mice were subjected to a six-week chronic unpredicted stress (CUS) paradigm. Then, the mice were treated with AC-5216 and tested with depressive and cognitive behaviours.Results: A single dose of AC-5216 (0.3 mg/kg) exerted anxiolytic- and antidepressant-like actions in TSPO WT mice. Moreover, in chronically stressed WT mice, two to four days of AC-5216 treatment (0.3 mg/kg, once per day) produced fast-onset antidepressant-like effects in the novelty-suppressed feeding and sucrose preference tests, as well as memory-enhancing effects in the novel object recognition test. In addition, a rapid (with five days of treatment) restoration of serum corticosterone levels and prefrontal cortex (PFC) allopregnanolone levels was found. Further studies showed that in these stress-exposed WT mice, AC-5216 significantly increased the levels of mTOR signalling-related proteins (mBDNF, p-mTOR, PSD-95, synapsin-1, GluR1), as well as the total dendritic length and branching points of pyramidal neurons in the PFC.Conclusions: These results suggest that TSPO mediates the fast-onset antidepressant-like and memory-enhancing effects of AC-5216, possibly through the rapid activation of mTOR signalling and restoration of dendritic complexity in the PFC. [ABSTRACT FROM AUTHOR]- Published
- 2020
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